Dialysis is the indicated treatment for patients whose kidney function is failing. The removal of waste substances from the blood is effected by transfer to an external fluid or replacement of plasma liquid by an external fluid. Various dialysis techniques, with associated dialysis fluids, can be differentiated, which are used depending on the type of patient. In the case of patients suffering from long-term renal insufficiency, the dialysis technique used is usually an intermittent treatment of few times (2 to 3 times) per week for a few hours (3 to 5 hours). With this technique, known as hemodialysis, waste substances, in particular urea, salts and other small molecules, are removed from the blood by means of diffusion through a semi-permeable membrane. Another form of dialysis is peritoneal dialysis. In contrast to hemodialysis, where the blood is passed over a dialysis fluid in a dialysis unit (artificial kidney) outside the body, in the case of peritoneal dialysis a dialysis fluid is introduced into a patient's abdominal cavity (peritoneum), wherein the peritoneum is acting as a semi-permeable membrane.
In the case of patients suffering from acute renal insufficiency, a continuous treatment, throughout the entire day for several weeks, a continuous renal replacement therapy (CRRT), is the indicated treatment. A technique other than hemodialysis, specifically hemofiltration, is used for this. In the case of hemofiltration, waste substances are removed from the blood by means of convective flow through a highly permeable membrane. In this way the above-mentioned waste substances are removed in larger amounts and large(r) molecules are also removed. In addition, in the case of hemofiltration and appreciable quantity of liquid, which can vary from 1 to 5 liters per hour, is removed from the bloodstream. In contrast to hemodialysis, this demands that in the case of hemofiltration a replacement fluid must be returned to the patient in large quantities. Optionally a combination of dialysis and filtration can be used. This is called hemodiafiltration. A specific type of hemodiafiltration is continuous veno-venous hemodiafiltration, abbreviation as CVVHDF.
Under certain circumstances, in patients receiving regular thrice-weekly hemodialysis treatments and more frequently in patients undergoing CRRT Hypophosphatemia could occur. In the first case it is mainly due to an excessive ingestion of phosphate binders, inadequate administration of phosphate salts in parenteral nutrition and continued removal of phosphorus by dialysis. In the second case it is mainly a consequence of the efficient removal of phosphorus from patients having normal renal function from the beginning and thus a normal serum phosphorus level.
Hypophosphatemia is prevented and treated principally via the oral and the intravenous routes, for example by ingestion of phosphorus-rich foodstuffs, by oral phosphorus preparations or by intravenous administration of sodium (or potassium) phosphate salts. However the administration of phosphorus via oral and intravenous routes must be carried out with great caution, since it is impossible to determine the precise magnitude of the total phosphorus deficit, it is difficult to decide the correct amount of phosphorus to be administered to the patient. If too much phosphorus is administered hyperphosphatemia might develop, having serious consequences for the patient, for example hypocalcemia, metastatic calcification and hypotensions, and if too little phosphorus is administered the hypophosphatemia is not corrected.
The solution containing both calcium ions and phosphate is used for total parenteral nutrition (TPN). The TPN solution is packed in multi-component bags with lipids in a first compartment, amino acids and phosphate and most of the electrolytes except calcium in a second compartment, and a third compartment containing calcium and glucose. The main difference compared to a medical solution according to the invention is that the pH of the final, ready-for-use solutions is much lower in the solutions according to this invention. The TPN solutions normally have a pH between 5.2-6.
In U.S. Pat. No. 6,743,191 a substitution infusion fluid is disclosed, which infusion fluid comprises among other 0.2-1.0 mM dihydrogen phosphate ions, preferably 0.5-0.9 mM, and 1.6-2.6 mM calcium ions, preferably 1.9-2.4. The substitution infusion fluid according to this disclosure may conveniently be prepared by dissolving salts in water in such amounts that the desired concentrations are reached, as is well within the expertise of the normal person skilled in the art. During the preparation it is desired that a sterile environment be maintained.
In U.S. Pat. No. 6,017,942 an intravenous solution for treating patient with chronic renal failure is disclosed, which solution comprises among other approximate 0-20 mM phosphate and approximate 0-10 mM calcium. This solution is to be administered 1-3 times per day.
The problem when introducing phosphorus in a medical solution is the formation of various calcium phosphates that precipitate and the risk for precipitation is further increased if the fluid is exposed to terminal heat sterilization. The solubility of calcium phosphates depends on the concentrations of calcium and phosphate, respectively, and further on the presence of other electrolytes, temperature and pH. As long as the pH is about 5.2-6, as in the TPN solutions, there is no risk of precipitation, but in physiological solutions with pH values equal to physiological pH of about 7-7.6, the risk of precipitation is enhanced. Accordingly, it is not only the pH during sterilization and storage that need to be controlled, also the pH in a mixed and ready-for-use solution needs to be controlled. The problem is also that many of these fluids should be stable during long-term storage, up to two years.
In one of the above-identified references this is solved by having the composition for the solution as a powder up until use and then dissolve it in a fluid before administration. However, even if trying to maintain sterility according to the European pharmacopoeia to thereby avoid the risk of infection in a patient, this is not an optimal way to maintain sterility. If a package is brought in connection with the atmosphere by e.g. injecting a solution component into a bag with a solution, this solution is no longer a sterile solution. Instead it is an aseptic solution, and aseptic solutions as such are not allowed to be infused into a patient.
The best way would be to have the solution terminal sterilized in its packaging in order to make sure that the solution is as sterile as possible and to be kept in this sterile environment also during mixing into a ready-for-use solution without opening up the bag and expose the content therein for contamination.